Direct gem‐Difluoroalkenylation of X−H Bonds with Trifluoromethyl Ketone N‐Triftosylhydrazones for Synthesis of Tetrasubstituted Heteroatomic gem‐Difluoroalkenes. Issue 22 (14th March 2022)

• Record Type: Journal Article
• Authors: Zhang, Xinyu; Li, Linxuan; Zanoni, Giuseppe; Han, Xinyue; Bi, Xihe
• Is Part Of: Chemistry. Volume 28:Issue 22(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-14
• Subjects: carbene -- difluoroalkene -- difluoroalkenylation -- rhodium catalysis -- silver catalysis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202200280
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The direct gem ‐difluoroalkenylation of X−H bonds represents the most straightforward approach to access heteroatomic gem ‐difluoroalkenes that, as the isostere of the carbonyl group, have great potency in drug discovery. However, the construction of tetrasubstituted heteroatomic gem ‐difluoroalkenes by this strategy is still an unsolved problem. Here, we report the first direct X−H bond gem ‐difluoroalkenylation of amines and alcohols with trifluoromethyl ketone N ‐triftosylhydrazones under silver (for (hetero)aryl hydrazones) or rhodium (for alkyl hydrazones), thereby providing a most powerful method for the synthesis of tetrasubstituted heteroatomic gem ‐difluoroalkenes. This method features a broad substrate scope, high product yield, excellent functional group tolerance, and operational simplicity (open air conditions). Moreover, the site‐specific replacement of the carbonyl group with a gem ‐difluorovinyl ether bioisostere in drug Trimebutine and the post‐modification of bioactive molecules demonstrates potential use in medicinal research. Finally, the reaction mechanism was investigated by combining experiments and DFT calculations, and disclosed that the key step of HF elimination occurred via five‐membered ring transition state, and the difference in the electrophilicity of Ag‐ and Rh‐carbenes as well as the multiple intermolecular interactions rendered the effectiveness of Rh catalyst selectively for alkyl hydrazones. Abstract : The first gem ‐difluoroalkenylation of amines and alcohols with trifluoromethyl ketone N ‐triftosylhydrazones is reported. This constitutes the most straightforward approach to access tetrasubstituted heteroatomic gem ‐difluoroalkenes in an efficient manner, featuring broad substrate scope, high yield, and excellent functional group tolerance.